title: Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I).
abstract: When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification.
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei-yang
authors.initials: MY
authors.lastname: Xi
authors.forename: Zhong-ying
authors.initials: ZY
authors.lastname: Sun
authors.forename: Hao-peng
authors.initials: HP
authors.lastname: Sun
authors.forename: Jian-min
authors.initials: JM
authors.lastname: Jia
authors.forename: Zheng-yu
authors.initials: ZY
authors.lastname: Jiang
authors.forename: Lei
authors.initials: L
authors.lastname: Tao
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Ya-jing
authors.initials: YJ
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Xue
authors.forename: Jing-jie
authors.initials: JJ
authors.lastname: Huang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Xiao-ke
authors.initials: XK
authors.lastname: Guo
authors.forename: Sheng-lie
authors.initials: SL
authors.lastname: Zhang
authors.forename: Ying-rui
authors.initials: YR
authors.lastname: Yang
authors.forename: Qing-long
authors.initials: QL
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Qi-dong
authors.initials: QD
authors.lastname: You
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020218:Response Elements / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D011753:Pyrones
keywords: ARE; Chemopreventive agents; Keap1; Nrf2; α-Pyrone derivative